EP1928820A2

EP1928820A2 - A process for preparing ester oxazolidine compounds and their conversion to florfenicol

Info

Publication number: EP1928820A2
Application number: EP06824884A
Authority: EP
Inventors: James C. Towson
Original assignee: Schering Plough Ltd Switzerland
Current assignee: Intervet International BV
Priority date: 2005-09-07
Filing date: 2006-08-31
Publication date: 2008-06-11
Anticipated expiration: 2026-08-31
Also published as: IL189828A0; ZA200802047B; AU2006287696A1; KR20080049040A; RU2008112952A; WO2007030386A2; JP2009507842A; IL189829A0; KR20080049039A; MX2008003187A; TWI331139B; JP5113754B2; WO2007030385A2; WO2007030385A3; ECSP088267A; WO2007030405A3; BRPI0615764A2; ZA200802046B; WO2007030405A2; EP1928820B1

Abstract

A process for preparing ester oxazolidine compounds is disclosed. These compounds are useful intermediates in processes for making Florfenicol.

Description

A Process for Preparing Ester Oxazolidine Compounds and Their Conversion to Florfenicol

Technical Field

The present invention relates generally to a new process for preparing oxazolidine protected aminodiol compounds. These compounds are useful intermediates in the process for making Florfenicol.

Background of the Invention

Florfenicol is a broad spectrum antibiotic of Formula I

Formula I

It has wide spread application in veterinary medicine for the treatment of both Gram positive and Gram negative bacteria as well as rickettsial infections. Florfenicol is also known as [R-(R*, S*)]-2,2-Dichloro-N-[1~(fluoromethyl)-2-hydroxy- 2-[4-(methylsulfonyl)phenyl]ethyl]acetamide. Commonly-assigned U.S. Patent No. 5,663,361 , the disclosure of which is incorporated herein by reference, describes the synthesis of Florfenicol intermediates and their use in processes for making Florfenicol. The primary advantage discussed therein is that the process eliminated the prior art's requirement to isolate the aminodiol sulfone (ADS) from the reaction vessel before proceeding with the Florfenicol synthesis.

More recently, U. S. Patent 2005/0075506 A1 described a process for preparing a compound of Formula Il that is useful as an intermediate in the synthesis of Florfenicol. Formula II

The process called for reacting the hydrochloride salt of an optically pure aminodiol compound of Formula III with acetone followed by acetyl chloride to give a compound of Formula II. The compound of Formula Il is then reacted further to give Florfenicol of Formula I.

Formula III

A major drawback of the process disclosed in 2005/0075506 A1 is the use of the aminodiol starting material of Formula III. The aminodiol compound of Formula III is expensive. It is also difficult to isolate and handle due to its amphoteric nature.

The present invention addresses this shortcoming and provides a still further alternative method of preparing useful intermediates included in the synthesis of Florfenicol.

SUMMARY OF THE INVENTION

In one embodiment, the present invention includes a process for preparing an oxazolidine protected aminodiol compound of Formula V: Formula V

wherein:

R₁ is hydrogen, methylthio, methylsulfoxy, methylsulfonyl, fluoromethylthio, fluoromethylsulfoxy, fluoromethylsulfonyl, nitro, fluoro, bromo, chloro, acetyl, benzyl, phenyl, halo substituted phenyl, C_1-6 alkyl, C_1-6 haloalkyl, C_3-8 cycloalkyl, C_2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, C_1-6 aralkyl, C_2-6 aralkenyl, or C_2-6 heterocyclic group;

R₂ is hydrogen, C_1-6 alkyl, C_1-6 haloalkyl, C_3-8 cycloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C-i_₆ alkoxy, C_1-6 aralkyl, C_2-6 aralkenyl, aryl, or C_2-6 heterocyclic group;

R₃ is hydrogen, C_1-6 alkyl, C_1-6 haloalkyl, C_3-8 cycloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, Ci_-6 alkoxy, C_1-6 aralkyl, C_2-6 aralkenyl, aryl or C_2-6 heterocyclic group; and

R4 is hydrogen, OH, C_1-6 alkyl, C_1-6 haloalkyl, C_3-8 cycloalkyl, benzyl, phenyl or C_1-6 phenylalkyl group, where the phenyl ring may be substituted by one or two halogens, Ci_-6 alkyl, or C_1-6 alkoxy. In another preferred embodiment, the present invention includes a process for preparing an oxazolidine protected aminodiol compound of Formula XII:

^{Formula XI1}

wherein:

R₁, R₂ and R₃ are as defined above; and R₇ is hydrogen, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 dihaloalkyl, C_1-6 trihaloalkyl, C_3-8 cycloalkyl, C_3-8 cyclohaloalkyl, C_3-8 cyclodihaloalkyl, C_3-8 cyclotrihaloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, Ci_-6 aralkyl, C_2-6 aralkenyl, C_2-6 heterocyclic, benzyl, phenyl or phenyl alkyl where the phenyl ring may be substituted by one or two halogens, C_1-6 alkyl or Ci_-6 alkoxy. Preferably, R₇ is CH₂CI, CHCI₂, CCI₃, CH₂Br, CHBr₂, CBr₃, CH₂F, CHF₂, or CF₃.

In one embodiment, the process includes the steps of: a) reacting a compound of Formula Vl:

Formula VI

wherein:

Ri is as defined above and R₅ is hydrogen, Ci_-6 alkyl, C_3-8 cycloalkyl, benzyl, phenyl or Ci_-6 phenylalkyl, in a vessel with a reducing agent in an alcoholic solvent to form an aminodiol compound of Formula VII:

Formula VII

wherein Ri is as defined above; b) reacting the aminodiol compound of Formula VII in the vessel without isolation (i.e., in situ) with an oxazolidine forming reagent to form a compound of Formula VIII:

Formula VIII

wherein Ri, R₂ and R₃ are as defined above; and c) reacting the compound of Formula VIII in the vessel without isolation (i.e., in situ) with a first N-acylating agent to form an oxazolidine protected aminodiol compound of Formula V.

In another preferred embodiment, the process includes the steps of: a) reacting a compound of Formula Vl in a vessel with an oxazolidine forming reagent to form the compound of Formula XIV:

Formula XIV

wherein R-i, R₂, R₃ and R₅ are as defined above; b) reacting the compound of Formula XIV in the vessel without isolation (i.e., in situ) with a reducing agent in an alcoholic solvent to form the compound of Formula VIII; c) reacting the compound of Formula VIII in the vessel without isolation (i.e., in situ) with a third N-acylating agent to form an oxazolidine protected aminodiol compound of Formula XII:

wherein R₁, R2, R3 and R₇ are as defined above; d) fluorinating the compound of Formula XII with a fluorinating agent in the presence of an organic solvent to obtain the compound of Formula XIII: Formula XIII

wherein Ri , R₂, R3 and R₇ are as defined above; e) selectively hydrolyzing the compound of Formula XIII with an acid or base catalyst to form the compound of Formula Xl:

Formula XI

wherein Ri and R₇ are as defined above; and f) if necessary, purifying the compound of Formula Xl with a mixture of a Ci- ₁₀ alkyl mono, di or tri alcohol and water to form the pure compound of Formula Xl.

Applicants have now surprisingly found significant processing advantages for forming the oxazolidine protected aminodiol compounds of Formula V and Formula XII. The compounds of Formula V, or specifically Formula II, are obtained when an ester precursor to the aminodiol free base compound of Formula III are used as starting materials. Such esters generally correspond to Formula Vl, and the ester of Formula IV is one particularly preferred ester:

Formula IV

The use of the esters of Formulas IV and Vl generates the expensive free base starting material of Formula III in situ, thereby eliminating the need to isolate this difficult to isolate compound. Yield losses for the free base starting material of Formula III due to isolation are thus eliminated with resulting increased yield and lower cost for the oxazolidine protected aminodiol compound of Formula V, or specifically the compound of Formula II. Applicants have also surprisingly found a more efficient process for making the compound of Formula XII by generating the compound of Formula XIV. After preparation of the compound of Formula XIV the compound can then be converted without isolation (i.e., in situ) and in the same reaction vessel to the compound of Formula XII by reduction and acylation. The compound of Formula XII can then be converted to a compound of Formula Xl, Florfenicol being the most preferred compound.

The present invention thus has the advantage of being an efficient and economical process for preparing Florfenicol, its analogs and oxazolidine intermediates related thereto.

DETAILED DESCRIPTION OF THE EMBODIMENTS

When utilized in the present specification and in the appended claims, the terms listed herein below, unless otherwise indicated, are defined as follows:

The term "alcoholic solvent" includes C₁ to C₁₀ alcohols such as methanol and ethanol and mixtures thereof, C-₂ to C_1O dialcohols such as ethylene glycol and Ci to C-iotrialcohols such as glycerin. Alternatively, the alcoholic solvent can be admixed with any suitable cosolvent. Such cosolvents can include other solvents which are miscible with the alcoholic solvent such as C₄ to Ci₀ alkanes, aromatic solvents such as benzene, toluene, xylenes, halobenzenes such as chlorobenzene, and ethers such as diethylether, tert-butylmethylether, isopropylether and tetrahydrofuran, or mixtures of any of the above solvents or cosolvents.

The term "alky!" means a straight or branched alkyl such as methyl, ethyl, propyl, or sec-butyl. Alternatively, the number of carbons in alkyl may be specified. For example, "C₁ to C₆ alkyl" means an "alkyl" as described above containing 1 to 6 carbon atoms. "Haloalkyl" means an "alkyl" as described above wherein one or more hydrogens are replaced by halo.

The term "aryl" means phenyl, or phenyl substituted by C₁ to C₆ alkyl or halo. "Substituted benzyl" means benzyl substituted by C₁ to C₆ alkyl or halo. The term "halo" means fluoro, chloro, bromo or iodo. The term "halo aryl" means phenyl substituted by halo. In one aspect of the invention, there is provided a process for preparing an oxazolidine protected aminodiol compound of Formula V:

Formula V

wherein:

Ri is hydrogen, methylthio, methylsulfoxy, methylsulfonyl, fluoromethylthio, fluoromethylsulfoxy, fluoromethylsulfonyl, nitro, fluoro, bromo, chloro, acetyl, benzyl, phenyl, halo substituted phenyl, Ci_-6 alkyl, Ci_-6 haloalkyl, C_3-8 cycloalkyl, C_2-6 alkenyl, C₂-₆ alkynyl, Ci_-6 alkoxy, Ci_₆ aralkyl, C2_-6 aralkenyl, or C2_-6 heterocyclic group;

R₂ is hydrogen, Ci_-6 alkyl, Ci_-6 haloalkyl, C_3-8 cycloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, Ci_-6 alkoxy, Ci_-6 aralkyl, C_2-6 aralkenyl, aryl, or C_2-6 heterocyclic group;

R₃ is hydrogen, Ci_-6 alkyl, Ci_-6 haloalkyl, C_3-8 cycloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, Ci_-6 alkoxy, Ci_-6 aralkyl, C_2-6 aralkenyl, aryl or C_2-6 heterocyclic group; and

R₄ is hydrogen, OH, Ci_-6 alkyl, Ci_-6 haloalkyl, C_3-8 cycloalkyl, benzyl, phenyl or Ci_₆ phenylalkyl group, where the phenyl ring may be substituted by one or two halogens, Ci_-6 alkyl or Ci_-6 alkoxy. The compounds corresponding thereto are useful intermediates in the formation of Florfenicol and related compounds.

One preferred process corresponding to the invention includes the steps of: a) reacting a compound of Formula Vl:

Formula VI

wherein:

Ri is as defined above and R₅ is hydrogen, C_1-6 alkyl, C_3-8 cycloalkyl, benzyl, phenyl or C_1-6 phenylalkyl, in a vessel with a reducing agent in an alcoholic solvent to form an aminodiol compound of Formula VII:

Formula VII

wherein R₁ is as defined above; b) reacting the aminodiol compound of Formula VIl in the vessel without isolation (i.e., in situ) with an oxazolidine forming reagent to form a compound of Formula VIII:

Formula VIII

wherein R-i, R₂ and R₃ are as defined above; and c) reacting the compound of Formula VIII in the vessel without isolation (i.e., in situ) with a first N-acylating agent to form an oxazolidine protected aminodiol compound of Formula V.

Within the general process described above, there are certain currently preferred aspects of the invention:

Ri is methylthio, methylsulfoxy, or methylsulfonyl. More preferably, Ri is methylsulfonyl;

R₂ and R₃ are hydrogen, methyl, ethyl or propyl. More preferably, R₂ and R₃ are methyl;

R₄ is a methyl, ethyl, propyl or isopropyl group. More preferably, R₄ is methyl; and R₅ is methyl, ethyl, n-propyl, isopropyl, butyl, t-butyl, or pentyl. The compound of Formula IV is commercially available. Alternative compounds corresponding to Formula Vl can be prepared using standard organic synthetic techniques without undue experimentation.

One preferred ester compound corresponding to Formula Vl is

In another aspect of the invention, the ester compound of Formula Vl is

Formula IVa

In still further aspects, the esters correspond to

Formula IVb

In a more preferred embodiment when Florfenicol is the desired end product, the compound corresponding to Formula Vl is the compound of Formula IV. As mentioned above, the first part of the process calls for reacting a compound of Formula Vl in a reaction vessel with a reducing agent. For purposes of the present invention, the term "reaction vessel" shall be understood to mean a container known to those of ordinary skill which is capable of holding the reactants and allowing the reaction step to proceed to completion. The size and type of vessel will, of course, depend upon the size of the batch and the specific reactants selected. A wide range of suitable reducing agents can be employed in carrying out the process of the invention. A non-limiting list of suitable reducing agents include NaBH₄, KBH₄, Ca(BH₄J₂, and LiBH₄ and mixtures thereof when an alcoholic solvent is used. The alcoholic solvent can also be one of many art-recognized solvents but some preferred solvents include methanol, ethanol, propanol, isopropanol, butanol and pentanol and mixtures thereof. One preferred reducing agent is KBH₄-

The molar ratio of reducing agent, such as KBH₄, to the compound of Formula IV is between about 1:1 and about 2:1. Preferably, when the reducing agent is

KBH₄, the molar ratio of KBH₄ to the compound of Formula IV is about 1.5:1 and the preferred solvent is methanol. This reduction can be carried out at a temperature of about 30⁰C to about 80⁰C in about 8 hours. Preferably, the temperature is below 6O⁰C and the time for the reaction to reach completion is under 6 hours. In an alternative aspect of the invention, the artisan can use reducing agents such as LiAIH₄ or NaAIH₄ when anhydrous conditions are desired. In such situations, solvents like ether or tetrahydrofuran can be used.

Once the aminodiol compound corresponding to Formula VII has been made, it is reacted, preferably in the same vessel (i.e., in situ), with an oxazolidine forming reagent such as formaldehyde, acetone, 2-methoxypropene, 2,2-dimethoxypropane, 2,2-diethoxypropane and mixtures thereof, under conditions such as those set forth in the examples to make a compound of Formula VIII. One preferred aminodiol compound corresponding to Formula VII is

Formula Vila

In a preferred embodiment when Florfenicol is the desired end product, the compound corresponding to Formula VIII is the compound:

Formula Villa

In a preferred embodiment, the methanol solvent is removed by distillation and replaced with another solvent designated herein as an oxazolidine forming solvent such as toluene, xylene, hexane or a mixture thereof. The preferred oxazolidine forming solvent is toluene. The ratio of the oxazolidine forming solvent to methanol is about 0.5:1 to 3:1 with the preferred ratio of about 1 :1. An oxazolidine forming reagent such as formaldehyde, acetone, 2-methoxypropene, 2,2- dimethoxypropane, 2,2-diethoxypropane and mixtures thereof is then added. One preferred oxazolidine forming reagent is acetone which is added in a ratio to toluene of about 0.5:1 to 3:1 with the preferred ratio of about 1 :1. The reaction runs to completion to form the oxazolidine compound of Formula VIII over about 12 - 18 hours in the presence of a base designated herein as an oxazolidine promoting base such as potassium carbonate, sodium carbonate, trimethylamine or triethylamine. A preferred base is potassium carbonate or triethylamine. The oxazolidine forming reaction can be carried out at a temperature of about 65 - 85°C. It is preferred that the compound of Formula VIII remain in the same vessel after completion of the reaction step when the first N-acylating agent is added. The nomeqclature "first," "second" and "third" are used for describing the (1) N-acylating (first) agents so as to distinguish the agents used for making the oxazolidine protected aminodiol compounds of Formula V, from the (2) N-acylating agents (second) which are used in the formation of the compounds of Formula Xl after the intermediate of Formula X has been formed, from the (3) N-acylating agents (third) used during the process to form the oxazolidine protected aminodiol compounds of Formula XII. Thus, some preferred first N-acylating compounds are of the formula R₆COR₄ wherein:

R₄ is hydrogen, OH, C_1-6 alkyl, C_1-6 haloalkyl, C_3-s cycloalkyl, benzyl, phenyl or C_1-6 phenylalkyl group, where the phenyl ring may be substituted by one or two halogens, C_1-6 alkyl or Ci_-6 alkoxy; and R₆ is halo, or Ci_-6 alkoxy. Some more preferred first acylating agents include acetyl chloride, acetyl bromide, propionyl chloride, propionyl bromide, butyl chloride, methyl chloroformate, ethyl chloroformate, propyl chloroformate and mixtures thereof. In a preferred embodiment when Florfenicol is the desired end product, the compound corresponding to Formula V is the compound:

In a preferred embodiment, a base such as potassium carbonate, sodium carbonate, trimethylamine or triethylamine is added in a molar equivalent ratio to the compound of Formula VII of about 1 :1 to 1 :3. The preferred base is potassium carbonate or triethylamine and the preferred molar equivalent ratio is about 1.1 to 1. The preferred first N-acylating agent acetyl chloride is added in a molar ratio to the compound of Formula VII of about 1 :1 to 3:1 with the preferred ratio being 1.1 :1. Reaction temperature is about 20 - 30⁰C and the reaction completes in about 2 - 4 hours.

After the oxazolidine protected aminodiol compound of Formula V has been prepared, it can be used in the synthesis of Florfenicol and related compounds. Thus, in a further aspect of the invention, the inventive process continues by fluorinating the compound of Formula V:

wherein Ri, R₂, R₃ and R₄ are as defined above, with a fluorinating agent in the presence of an organic solvent to obtain a compound of Formula IX:

Formula IX

wherein Ri, R₂, R₃ and R₄ are as defined above.

In one preferred aspect of this embodiment when Florfenicol is the desired end product, the compound corresponding to Formula IX is specifically:

Suitable fluorinating agents include, without limitation, N-(2-chloro-1 ,1 ,2- trifluoroethyl)diethylamine, N-(2-chloro-1 ,1 ,2-trifluoroethyl)dimethylamine, N-(2- chloro-1 ,1 ,2-trifluoroethyl)dipropylamine, N-(2-chloro-1 ,1 ,2-trifluoroethyl)pyrrolidine, N-(2-chloro-1 ,1 ,2-trifluoroethyl)-2-methylpyrrolidine, N-(2-chloro-1 ,1 ,2-trifluoroethyl)- 4-methylpiperazine, N-(2-chloro-1 ,1 ,2-trifluoroethyl)-morpholine, N-(2-chloro-1 ,1 ,2- trifluoroethyl)piperidine, 1,1,2,2-tetrafluoroethyl-N,N-dimethylamine, (Diethylamino) sulfur trifluoride, Bis-(2-methoxyethyl)aminosulfur trifluoride, N,N-diethyl-1 ,1 ,2,3,3,3- hexafluoro-1-propanamine (Ishikawa Reagent) and mixtures thereof. One preferred fluorinating agent is N,N-diethyl-1 ,1 ,2,3,3,3-hexafluoro-1-propanamine.

The molar ratio of the fluorinating agent such as N, N-diethyl-1 , 1 ,2,3,3,3- hexafluoro-1 -propanamine to the compound according to Formula V is between about 1 :1 and about 2:1. Preferably, the molar ratio of the N,N-diethyl-1 ,1 ,2,3,3,3- hexafluoro-1 -propanamine to the compound of Formula V is about 1.5:1. The fluorinating step can be carried out at a temperature of from about 8O⁰C to about 110⁰C and at a pressure of about 60 psi. The organic solvent used during the fluorinating step is preferably 1 ,2- dichloroethane, methylene chloride, chloroform, chlorobenzene, chlorinated hydrocarbons or mixtures thereof. A more preferred organic solvent is methylene chloride.

After the compound of Formula IX has been made, it is hydrolyzed with acid to form the compound of Formula X: Formula X

wherein R₁ is as defined above, preferably, Ri is CH₃SO₂.

The acid used in this part of the process can be an inorganic acid like aqueous hydrochloric acid, sulfuric acid, or phosphoric acid or an organic acid like methanesulfonic acid. The hydrolyzing step is preferably carried out by heating the compound of Formula IX with 6N aqueous hydrochloric acid at a temperature of from about 90⁰C to about 105°C for about 60 minutes. Other suitable hydrolyzing steps will be apparent to those of ordinary skill.

In one preferred aspect of this embodiment when Florfenicol is the desired end product, the compound corresponding to Formula X is:

Formula Xa

After hydrolysis has been completed, the compound of Formula X is reacted without isolation (Ae., in situ) with a second N-acylating agent to make compounds of Formula Xl:

Formula XI

wherein R₁ is the same as above, preferably CH₃SO₂; and R₇ is hydrogen, Ci_-6 alkyl, C_1-6 haloalkyl, C_1-6 dihaloalkyl, C_1-6 trihaloalkyl, C_3-8 cycloalkyl, C_3-8 cyclohaloalkyl, C_3-8 cyclodihaloalkyl, C_3-8 cyclotrihaloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-B alkoxy, C_1-6 aralkyl, C_2-6 aralkenyl, C_2-6 heterocyclic benzyl, phenyl or phenyl alkyl where the phenyl ring may be substituted by one or two halogens, Ci_-6 alkyl or Ci_-6 alkoxy. Preferably, R₇ is CH₂CI, CHCI₂, CCI₃, CH₂Br, CHBr₂, CBr₃, CH₂F, CHF₂, or CF₃. Thus, one preferred compound of Formula Xl is:

³ Formula XIa

wherein R₇ is as defined above.

In one preferred aspect of this embodiment when Florfenicol is the desired end product, the compound corresponding to Formula Xl is the compound of Formula I:

Suitable second N-acylating compounds are of the formula R₈COR₇, wherein R₇ is the same as that described above and Rs is OH, halo or Ci_-6 alkoxy. Some more preferred second N-acylating agents include dichloroacetic acid or a reactive derivative thereof. A non-limiting list includes reagents such as methyldichloroacetate, ethyldichloroacetate, or dichloroacetylchloride.

The second N-acylation step is preferably carried out by reacting the compound of Formula X in methanol with methyldichloroacetate at a temperature of from about 2O⁰C to about 30⁰C for about 12 hours.

After the compound of Formula Xl is made and if necessary, the compound of Formula Xl can optionally be purified by heating in a mixture of an alkyl mono, di or tri alcohols and water. The alcohols in this part of the process can be Ci.i₀ monoalcohols, Ci_i₀dialcohols and C_1-I₀ trialcohols and mixtures thereof. A non- limiting list of the C_1-10 monoalcohols includes methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, t-butanol and pentanol. One preferred Ci_-10 monoalcohol is isopropanol. A non-limiting list of the C_1-10 dialcohols includes ethylene glycol, propylene glycol and butylene glycol of which propylene glycol is preferred. Glycerin is the preferred C_1-10 trialcohol. A C_1-10 monoalcohol is preferred for the purification. One most preferred C_1-10 monoalcohol is isopropanol.

The ratio of alcohol, such as isopropanol, to water is between 1:5 and 5:1. Preferably, when the alcohol is isopropanol, the ratio of isopropanol to water is 1 :1. The compound of Formula Xl is dissolved in a 1 :1 mixture of isopropanol and water heated to the reflux point of the mixture. The solution is clarified by filtration with active carbon and a filter aid, then cooled to about 10 - 30⁰C and the purified compound of Formula Xl crystallizes from solution. Preferably, the solution is cooled to about 20 - 25°C and the purified compound of Formula Xl crystallizes from solution. In a preferred embodiment when Florfenicol is the desired end product, the purified compound corresponding to Formula Xl is the compound of Formula I.

In another preferred embodiment, the process corresponding to the invention includes the steps of: a) reacting a compound of Formula Vl in a vessel with an oxazolidine forming reagent to form the compound of Formula XIV:

Formula XIV

wherein R₁, R₂, R₃ and R₅ are as defined above; b) reacting the compound of Formula XIV in the vessel without isolation (i.e., in situ) with a reducing agent in an alcoholic solvent to form a compound of Formula VIII: Formula VIII

wherein R-i, R₂ and R₃ are as defined above; c) reacting the compound of Formula VIII in the vessel without isolation (i.e., in situ) with a third N-acylating agent to form an oxazolidine protected aminodiol compound of Formula XII:

Formula XII

wherein Ri , R₂, R₃ and R₇ are as defined above; d) fluorinating the compound of Formula XII with a fluorinating agent in the presence of an organic solvent to obtain a compound of Formula XIII:

Formula XIII

wherein R-i, R₂, R₃ and R₇ are as defined above; e) selectively hydrolyzing the compound of Formula XIII with an acid or base catalyst to form the compound of Formula Xl: Formula XI

wherein Ri and R₇ are as defined above; and f) if necessary, purifying the compound of Formula Xl with a mixture of a Ci- io alkyl mono, di or tri alcohol and water to form the pure compound of Formula Xl.

In the preferred embodiment described above, there are certain preferred aspects of the invention. One preferred aspect is that the compound of Formula Vl reacts in a vessel with an oxazolidine forming reagent. A wide range of suitable oxazolidine forming reagents can be employed in carrying out the invention. A non- limiting list of suitable oxazolidine forming reagents include formaldehyde, acetone, 2-methoxypropene, 2,2-dimethoxypropane, 2,2-diethoxypropane and mixtures thereof. The solvent for the formation of compounds of Formula XIV can be the oxazolidine forming agent itself or a suitable organic solvent. Such solvents include but are not limited to alcoholic solvents such as methanol, ethanol, propanol, isopropanol, butanol, pentanol and mixtures thereof.

In a preferred embodiment, the oxazolidine forming reagent is added to the compound of Formula Vl in an alcoholic solvent. The preferred oxazolidine forming reagent is 2,2-dimethoxypropane. 2,2-Dimethoxypropane is added to the compound of Formula Vl in a ratio of between 1 :1 and 5:1 with the preferred ratio of about 1:1. The preferred alcoholic solvent is methanol. The reaction runs to completion to form the ester oxazolidine compound of Formula XIV in the presence of a base designated herein as an ester oxazolidine promoting base such as lithium carbonate, lithium hydroxide triethylamine or trimethylamine. A preferred base is lithium carbonate. The ester oxazolidine forming reaction can be carried out at a temperature of less than 8O⁰C.

In a preferred embodiment when Florfenicol is the desired end product, the compound corresponding to Formula XIV is the compound of Formula XIVa: Formula XIVa

Preferably, the compound of Formula XIV remains in the same vessel after completion of the ester oxazolidine reaction when the reducing agent is added. A wide range of suitable reducing agents can be employed in carrying out the process of the invention to form the compound of Formula VIII. A non-limiting list of suitable reducing agents include NaBH₄, KBH₄, Ca(BH₄)₂, and LiBH₄ and mixtures thereof when an alcoholic solvent is used. The alcoholic solvent can also be one of many art-recognized solvents but some preferred solvents include methanol, ethanol, propanol, isopropanol, butanol and pentanol and mixtures thereof. One preferred reducing agent is KBH₄.

The molar ratio of reducing agent, such as KBH₄, to the compound of Formula Vl is between about 1 :1 and about 2:1. Preferably, when the reducing agent is KBH₄, the molar ratio of KBH₄ to the compound of Formula Vl is about 1.5:1 and the preferred solvent is methanol. This reduction can be carried out at a temperature of about 30°C to about 80⁰C in about 8 hours. Preferably, the temperature is below 6O⁰C and the time for the reaction to reach completion is under 6 hours.

In an alternative aspect of the invention, the artisan can use reducing agents such as LiAIH₄ or NaAIH₄ when anhydrous conditions are desired. In such situations, solvents like ether or tetrahydrofuran can be used.

In a preferred embodiment when Florfenicol is the desired end product, the compound corresponding to Formula VIII is the compound of Formula Villa: Formula Villa

It is preferred that after the compound of Formula VIII is made it is reacted preferably in the same vessel (i.e., in situ) with a suitable third N-acylating compound to form the compound of Formula XII. Some preferred third N-acylating compounds are of the formula R₆COR₇, wherein R₆ and R₇ are as defined above. In a preferred embodiment, R₆ is Cl and R₇ is CH₂CI, CHCI₂, CCI₃, CH₂Br, CHBr₂, CBr₃, CH₂F, CHF₂, or CF₃.

Some preferred third N-acylating agents include alkylhaloacetic acid derivatives. A non-limiting list includes reagents such as methyldichloroacetate, ethyldichloroacetate, dichloroacetylchloride, methylchloroacetate, ethylchloroacetate, chloroacetylchloride, methyltrichloroacetate, ethyltrichloroacetate, trichloroacetylchloride, methyldifluoroacetate, ethyldifluoroacetate, difluoroacetylchloride, methylfluoroacetate, ethylfluoroacetate, fluόroacetylchloride, methyltrifluoroacetate, ethyltrifluoroacetate, trifluoroacetylchloride, dichloroacetylbromide, difluoroacetylbromϊde, acetylchloride and acetylbromide.

In a preferred embodiment when Florfenicol is the desired end product, the compound corresponding to Formula XII is the compound of Formula XIIa:

In a preferred embodiment, a base such as potassium carbonate, sodium carbonate, trimethylamine or triethylamine is added in a molar equivalent ratio to the compound of Formula Villa of about 1 :1 to 1 :3. The preferred base is potassium carbonate or triethylamine and the preferred molar equivalent ratio is about 1.1 to 1. The preferred N-acylating agent dichloroacetyl chloride is added in a molar ratio to the compound of Formula Villa of about 1 :1 to 3:1 with the preferred ratio being 1.1 :1. Reaction temperature is about 20 - 30⁰C and the reaction completes in about 2- 4 hours.

After the oxazolidine protected aminodiol compound of Formula XII has been prepared, it can be used in the synthesis of Florfenicol and related compounds. Thus, in a further aspect of the invention, the inventive process continues by fluorinating the compound of Formula XII:

Formula XII

wherein R₁, R₂, R₃ and R₇ are as defined above, with a fluorinating agent, as previously defined, in the presence of an organic solvent, as previously defined, to obtain a compound of Formula XIII:

Formula XIII

wherein Ri, R₂, R₃ and R₇ are as defined above.

In one preferred aspect of this embodiment when Florfenicol is the desired end product, the compound corresponding to Formula XIII is specifically the compound of Formula XIIIa: Formula XIIIa

After the compound of Formula XIII has been made, it is selectively hydrolyzed with acid or base catalyst to form the compound of Formula Xl:

Formula XI

wherein Ri and R₇ are as defined above. Preferably, Ri is methylsulfonyl and

R₇ is CH₂CI, CHCI₂, CCI₃, CH₂Br, CHBr₂, CBr₃, CH₂F, CHF₂, or CF₃.

A wide range of acid catalysts can be employed in carrying out the process of the invention. A non-limiting list of suitable acid catalysts include inorganic acids like dilute aqueous hydrochloric acid, sulfuric acid, or phosphoric acid or organic acids like methanesulfonic acid or p-toluene sulfonic acid. One preferred acid catalyst is p-toluene sulfonic acid. Similarly, a wide range of basic catalysts can be employed in carrying out the process of the invention. A non-limiting list of suitable basic catalysts include inorganic bases such as LiOH, NaOH, KOH, Li₂CO₃, Na₂CO₃, K₂CO₃ or organic bases such as sodium methoxide, sodium ethoxide, potassium methoxide and potassium ethoxide. One preferred basic catalyst is K₂CO₃. The selective hydrolyzing step is preferably carried out be heating the compound of Formula XIII with p-toluene sulfonic acid in a mixture of an organic solvent and water at a temperature below 80⁰C. One preferred organic solvent is methylene chloride. Other suitable selective hydrolyzing steps will be apparent to those of ordinary skill.

In one preferred aspect of this embodiment when Florfenicol is the desired end product, the compound corresponding to Formula Xl is the compound of Formula I. After the compound of Formula Xl is made and if necessary, it can optionally be purified by the process as described above. In a preferred embodiment when Florfenicol is the desired end product, the purified compound corresponding to Formula Xl is the compound of Formula I.

EXAMPLES

The following preparative examples of preferred novel derivatives serve to provide further appreciation of the invention but are not meant in any way to restrict the effective scope of the invention. Example 1

Preparation of (4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4- (methylsulfonyl)phenyl]-1 ,3-oxazolidine (Compound II) (2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate

(Compound IV) (100 g, 0.3480 moles) in 500 ml_ of methanol reacts with potassium borohydride (28.2 g, 0.5220 moles) over 4 - 8 hours at 50 - 60⁰C to quantitatively yield (1 R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propandiol (Compound VII: Ri is methylsulfonyl) (85.36 g, 0.3480 moles) in solution. Toluene (500 ml_) and acetone (500 ml_) replace methanol which distills off. Addition of potassium carbonate (6.9 g, 0.0696 moles) with heating at 75 - 85°C for 12 - 18 hours yields (4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1 ,3-oxazolidine (Compound VIII: R₁ is methylsulfonyl and R₂ and R₃ are methyl). Addition of potassium carbonate (19.0 g, 0.1914 moles) and acetyl chloride (30.0 g, 0.3828 moles) at 20 - 25°C for 2 - 4 hours then addition of water (500 ml_) precipitates the crude product. Filtration, washing with water (250 ml_) then drying yields (4R,5R)-3- acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyI)phenyl]-1 ,3-oxazolidine (Compound II).

Example 2

(Compound IV) (100 g, 0.3480 moles) in methanol (450 ml_) reacts with potassium borohydride (28.2 g, 0.5220 moles) over 4 - 8 hours at 50 - 60⁰C to quantitatively yield (1 R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1 ,3-propandiol (Compound VII: R₁ is methylsulfonyl) (85.4 g, 0.3480 moles) in solution. Toluene (450 ml_) and acetone (450 ml_) replace methanol which distills off. Addition of triethylamine (8.8 g, 0.0870 moles) with heating at 70 - 80⁰C for 12 - 18 hours yields (4R,5R)-2,2- dimethyI-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1 ,3-oxazolidine (Compound VIII: Ri is methylsulfonyl and R₂ and R₃ are methyl). Addition of triethylamine (44.5 g, 0.4402 moles) and acetyl chloride (30.0 g, 0.3828 moles) at 20 - 25°C for 2 - 4 hours then addition of water (500 ml_) precipitates the crude product. Filtration, washing with water (200 ml_) then drying yields (4R,5R)-3-acetyl-2,2-dimethyl-4- hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1 ,3-oxazolidine (Compound II).

Example 3 Preparation of (4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4- (methylsulfonyl)phenyl]-1 ,3-oxazolidine (Compound M)

(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound IV) (100 g, 0.3480 moles) in tetrahydrofuran (500 ml_) reacts with lithium aluminum hydride (16.0 g, 0.4224 moles) over 4 - 8 hours at 60 - 70°C to quantitatively yield (1 R,2R)-2-amino-1-[4-methylsulfonyl)phenyl]-1 ,3-propandiol (Compound VII: Ri is methylsulfonyl) (85.36 g, 0.3480 moles). Addition of ethyl acetate (75 ml_) destroys any excess lithium aluminum hydride. Addition of xylene (600 imL), 2-methoxypropene (37.6 g, 0.5220 moles), and p-toluenesulfonic acid monohydrate (6.6 g, 0.0348 moles) with agitation at 20 - 30⁰C for 10 - 16 hours produces (4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1 ,3- oxazolidine (Compound VIII: Ri is methylsulfonyl and R₂ and R₃ are methyl). Addition of triethylamine (81.3 g, 0.8039 moles) and acetyl chloride (30.0 g, 0.3828 moles) at 20 - 25°C for 2 - 4 hours then addition of water (650 ml_) precipitates the crude product. Filtration, washing with water (300 ml_) then drying yields (4R,5R)-3- acetyl-2,2-dimethyi-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1 ,3-oxazolidine (Compound II). Example 4

Preparation of (4R,5R)-3-propionyl-2,2-dimethyl-4-hydroxymethyl-5-[4- (methylsulfonyl)phenyl]-1 ,3-oxazolidine (Compound V: R-i is methylsulfonyl, R₂ and R₃ are methyl and R₄ is ethyl)

(2S,3R)-Methyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound Vl: R₁ is methylsulfonyl and R₅ is methyl) (75 g, 0.2744 moles) in 350 ml_ of methanol reacts with sodium borohydride (16.6 g, 0.4390 moles) over 4 - 8 hours at 50 - 60⁰C to quantitatively yield (1 R,2R)-2-amino-1 -[4- methylsulfonyl)phenyl]-1 ,3-propandiol (Compound VII: R₁ is methylsulfonyl) (67.31 g, 0.2744 moles) in solution. Addition of 20% hydrochloric acid and 2,2- dimethoxypropane (35.7 g, 0.3430 moles) with agitation at 25 - 35°C for 3 - 5 hours then addition of xylene (650 ml_) and heating to 75 - 85°C for a further 12 - 16 hours yields (4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1 ,3- oxazolidine (Compound VIII: R₁ is methylsulfonyl and R₂ and R₃ are methyl). Addition of triethylamine (52.1g, 0.5145 moles) and propionyl chloride (31.7 g, 0.3430 moles) at 20 - 25°C for 2 - 4 hours then addition of water (625 mi_) precipitates the crude product. Filtration, washing with water (300 ml_) then drying yields (4R,5R)-3-propionyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)- phenyl]-1 ,3-oxazolidine (Compound V: R₁ is methylsulfonyl, R₂ and R₃ are methyl and R₄ is ethyl).

Example 5

Preparation of (4S,5R)-3-acetyl-2,2-dimethyl-4-fluoromethyl-5-[4- (methylsulfonyl)phenyl]-1 ,3-oxazolidine (Compound IX: R₁ is methylsulfonyl; R₂, R₃ and R₄ are methyl) (4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1 ,3- oxazolidine (Compound II) (75 g, 0.2291 moles) in methylene chloride (525 ml) reacts with N,N-diethyl-1 ,1,2,3,3,3-hexafluoro-1-propanamine (Ishikawa Reagent) (76.7 g, 0.3437 moles) at 95 - 105⁰C for about 4 hours. Cooling to 20 - 25°C, addition to sodium hydroxide (6 g) in water (2500 mL), separation of the methylene chloride layer, distillation and replacement of methylene chloride by isopropanol (750 mL), precipitates the desired product. Filtration, washing with water (100 mL) and isopropanol (75 mL), then drying yields (4S,5R)-3-acetyl-2,2-dimethyl-4-fluoromethyl- 5-[4-(methylsulfonyl)phenyl]-1 ,3-oxazolidine (Compound IX: Ri is methylsulfonyl; R₂, R₃ and R₄ are methyl).

Example 6

Preparation of (4S,5R)-3-propionyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methyl- suϊfonyl)phenyl]-1 ,3-oxazolidine (Compound IX: Ri is methylsulfonyl, R₂ and R₃ are methyl and R₄ is ethyl) (4R,5R)-3-propionyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1 ,3- oxazolidine (Compound V: Ri is methylsulfonyl, R₂ and R₃ are methyl and R₄ is ethyl) (70 g, 0.2050 moles) in methylene chloride (450 ml) reacts with N,N-diethyl- 1 ,1 ,2,3,3,3-hexafluoro-1-propanamine (Ishikawa Reagent) (73.2 g, 0.328 moles) at 95 - 105⁰C for 2 - 4 hours. Cooling to 20 - 25°C, quenching with 25% aqueous sodium hydroxide and water (2000 ml_) and separation of the methylene chloride layer gives a solution of (4S,5R)-3-propionyl-2,2-dimethyl-4-fluoromethyl-5-[4- (methylsulfonyl)phenyl]-1 ,3-oxazolidine (Compound IX: R₁ is methylsulfonyl, R₂ and R₃ are methyl and R₄ is ethyl) for use in the next step.

Example 7

Preparation of (1 R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1- propanol (Florfenicol) (4S,5R)-3-acetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1 ,3- oxazolidine (Compound IX: Ri is methylsulfonyl; R₂, R₃ and R₄ are methyl) (50.0 g, 0.1518 moles) hydrolyses in water (300 ml_) containing 20% hydrochloric acid at 90 to 100⁰C over about 1 hour. Adjusting the pH to greater than 12 by addition of sodium hydroxide and extraction with methylene chloride (500 mL) yields (1 R,2S)-1- [4-(methylsulfonylphenyl]-2-amino-3-fluoro-1-propanol (Compound Xa) in solution. Methanol (100 mL) replaces methylene chloride which distills off. Addition of methyl dichloroacetate (65.1 g, 0.4554 moles) and triethylamine (16.1 g, 0.1594 moles) with agitation for 12 - 16 hours at 20 - 25°C then addition of water (175 mL) and toluene (100 mL) precipitates the product. Filtration, washing with water (100 mL) and toluene (175 mL) then drying yields (1 R,2S)-2-dichloroacetamido-3-fluoro-1-[4- (methylsulfonyl)phenyl]-1 -propanol (Florfenicol). Example 8

Preparation of (1 R^S^-dichloroacetamido-S-fluoro-i-^methylsulfonyOphenylJ-i- propanol (Florfenicol)

(4S,5R)-3-acetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1 ,3- oxazolidine (Compound IX: Ri is methylsulfonyl; R₂, R₃ and R₄ are methyl) (50.0 g, 0.1518 moles) hydrolyses in water (300 mL) containing 20% hydrochloric acid at 90 to 100⁰C over about 1 hour. Adjusting the pH to greater than 12 by addition of sodium hydroxide and extraction with methylene chloride (500 mL) yields (1 R,2S)-1- [4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol (Compound Xa) in solution. Addition of triethylamine (16.9g, 0.1670 moles) and dichloroacetyl chloride (24.6 g, 0.1670 moles) at 20 - 30⁰C for 4 - 6 hours then removal of methylene chloride by distillation and replacement by toluene (350 mL) and water (100 mL) precipitates the product. Filtration, washing with water (150 mL) and toluene (150 mL) then drying yields (1 R,2S)-2-dichloroacetamido-3-fluoro-1 -[4-(methylsulfonyl)phenyl]-1 -propanol (Florfenicol).

Example 9

Purification of (1 R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1- propanol (Florfenicol)

(1 R,2S)-2-dichloroacetamido-3-fluoro-1 -[4-(methylsulfonyl)phenyl]-1 -propanol (Florfenicol) (45 g, 0.1256 moles) dissolves in water (115 mL) and isopropanol (115 mL) at reflux. Cooling to 20 - 25°C, filtration of the solids, washing with 1 to 1 water/isopropanol (50 mL) then drying gives pure (1 R,2S)-2-dichloroacetamido-3- fluoro-1 -[4-(methylsulfonyl)phenyl]-1 -propanol (Florfenicol).

Example 10

Preparation and Purification of (1 R,2S)-2-dichloroacetamido-3-fluoro-1-[4- (methylsulfonyl)phenyl]~1 -propanol (Florfenicol) (4S,5R)-3-acetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1 _>3- oxazolidine (Compound IX: Ri is methylsulfonyl; R₂, R₃ and R₄ are methyl) (50.0 g, 0.1518 moles) hydrolyses in water (300 mL) containing 20% hydrochloric acid at 90 to 100⁰C over about 1 hour. Washing with methylene chloride (200 mL), adjusting the pH to greater than 12 by addition of sodium hydroxide and extraction with methylene chloride (300 mL) yields (1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3- fluoro-1-propanol (Compound Xa) in solution. Methanol (100 mL) replaces methylene chloride which distills off. Addition of methyl dichloroacetate (65.1 g, 0.4554 moles) and triethylamine (16.1 g, 0.1594 moles) with agitation for 12 - 16 hours at 20 - 25°C then addition of water (175 mL) and toluene (100 mL) precipitates the crude product. Filtration, washing with water (100 mL) and toluene (174 mL) then dissolution in water (115 mL) and isopropanol (115 mL) at reflux, cooling to 20 - 25°C, filtration of the solids, washing with 1 to 1 water/isopropanol (50 mL) then drying gives pure (1 R,2S)-2-dichloroacetamido-3-fluoro-1-[4- (methylsulfonyl)phenyl]-1 -propanol (Florfenicol).

Example 11 Preparation and Purification of (1 R,2S)-2-dichloroacetamido-3-fluoro-1-[4- (methylsulfonyl)phenyl]-1 -propanol (Florfenicol)

Methylene chloride (450 mL) distills from a solution of (4S,5R)-3-propionyl-2,2- dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1 ,3-oxazolidine (Compound IX: Ri is methylsulfonyl, R₂ and R₃ are methyl, and R₄ is ethyl) (50.Og, 0.1456 moles) after addition of water (300 mL) containing 20% hydrochloric acid and heating to 90 - 100⁰C for 2 - 4 hours. Adjusting the pH to greater than 12 by addition of sodium hydroxide and extraction with methylene chloride (350 mL) yields a solution of (1 R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1 -propanol (Compound Xa). Methanol (150 mL) replaces methylene chloride which distills off. Addition of methyl dichloroacetate (52.0 g, 0.3640 moles) and triethylamine (11.0 g, 0.1092 moles) with agitation for 12 - 16 hours at 20 - 25°C then addition of water (150 mL) and toluene (100 mL) precipitates the crude product. Filtration, washing with water (75 mL) and toluene (125 mL) then dissolution in water (50 mL) and isopropanol (100 mL) at reflux, cooling to 20 - 25°C, filtration of the solids, washing with 1 to 1 water/isopropanol (50 mL) then drying gives pure (1 R,2S)-2-dichloroacetamido-3- fluoro-1 -[4-(methylsulfonyl)phenyl]-1 -propanol (Florfenicol). Example 12

Preparation of (4R,5R)-3-dichloroacetyl-2,2-dimethyl-4-hydroxymethyl-5-[4- (methylsulfonyl)phenyl]-1 ,3-oxazolidine (Compound XIIa)

(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate

(Compound IV) (100 g, 0.3480 moles) in 500 ml_ of methanol reacts with 2,2- dimethoxypropane (39.9 g, 0.3828 moles) and lithium carbonate at 60 - 7O⁰C to yield (4S,5R)-2,2-dimethyl-4-ethylcarboxyl-5-[4-(methylsulfonyl)phenyl]-1 ,3- oxazolidine (Compound XIVa) (113.9 g, 0.3480 moles). Addition of potassium borohydride (28.2 g, 0.5220 moles) with stirring over 4 - 8 hours at 50 - 60⁰C then yields (4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1 ,3- oxazolidine (Compound Villa). Addition of potassium carbonate (19.0 g, 0.1914 moles) and dichloroacetyl chloride (56.4 g, 0.3828 moles) at 20 - 25°C for 2 - 4 hours then addition of water (500 ml_) precipitates the crude product. Filtration, washing with water (250 ml_) then drying yields (4R,5R)-3-dichloroacetyl-2,2- dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1 ,3-oxazolidine (Compound XIIa).

Example 13

Preparation of (4S,5R)-3-dichloroacetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methyl- sulfonyl)phenyl]-1 ,3-oxazolidine (Compound XIIIa) (4R,5R)-3-dichloroacetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]- 1 ,3-oxazolidine (Compound XIIa) (81 g, 0.2050 moles) in methylene chloride (450 ml) reacts with N,N-diethyl-1 ,1 ,2,3,3,3-hexafluoro-1-propanamine (Ishikawa Reagent) (73.2 g, 0.328 moles) at 95 - 105°C for 2 - 4 hours. Cooling to 20 - 25°C, quenching with 25% aqueous sodium hydroxide and water (2000 ml_) and separation of the methylene chloride layer gives a solution of (4S,5R)-3-dichloroacetyl-2,2- dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1 ,3-oxazolidine (Compound XIIIa) for use as an intermediate for the next step in the process.

Example 14 Preparation of (1 R,2S)-2-dichloroacetamido-3-fluoro-1 -[4-(methylsulfonyl)phenyl]-1 - propanol (Florfenicol) (4S,5R)-3-dichloroacetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]- 1 ,3-oxazolidine (Compound XIIIa) (60.5 g, 0.1519 moles) selectively hydrolyses in methylene chloride (300 ml_) and water (100 ml_) containing p-toluene sulfonic acid at 60⁰C over several hours. Removal of the methylene chloride by distillation and cooling to 20 - 25°C precipitates the product. Filtration, washing with water (100 ml_) and toluene (100 ml_) then drying yields (1 R,2S)-2-dichloroacetamido-3-fluoro-1- [4-(methylsulfonyl)phenyl]-1 -propanol (Florfenicol).

Claims

What is claimed is:

1. A process for preparing a compound of Formula Xl:

Formula XI

wherein:

Ri is hydrogen, methylthio, methylsulfoxy, methylsulfonyl, fluoromethylthio, fluoromethylsulfoxy, fluoromethylsulfonyl, nitro, fluoro, bromo, chloro, acetyl, benzyl, phenyl, halo substituted phenyl, Ci_-6 alkyl, Ci_-6 haloalkyl, C_3-8 cycloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, Ci_-6 aralkyl, C_2-6 aralkenyl, or C_2-6 heterocyclic group; and

R₇ is hydrogen, Ci_-6 alkyl, Ci_-6 haloalkyl, Ci_-6 dihaloalkyl, Ci trihaloalkyl, C_3-8 cycloalkyl, C_3-8 cyclohaloalkyl, C_3-8 cyclodihaloalkyl, C_3-8 cyclotrihaloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, Ci_-6 alkoxy, Ci_-6 aralkyl, C_2-6 aralkenyl, C_2-6 heterocyclic benzyl, phenyl or phenyl alkyl where the phenyl ring may be substituted by one or two halogens, Ci_-6 alkyl or Ci_-6 alkoxy comprising: a) reacting a compound of Formula Vl:

Formula VI

wherein:

Ri is as defined above;

R₅ is hydrogen, Ci_-6 alkyl, C_3-8 cycloalkyl, benzyl, phenyl or Ci_-6 phenylalkyl with an oxazolidine forming reagent to form a compound of Formula XIV: Formula XIV

wherein:

R₁ and R₅ are as defined above; R₂ is hydrogen, C_1-6 alkyl, C1-6 haloalkyl, C_3-8 cycloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, Ci_-6 alkoxy, Ci_-6 aralkyl, C2-6 aralkenyl, aryl, or C_2-6 heterocyclic group; R₃ is hydrogen, C_1-6 alkyl, C_1-6 haloalkyl, C_3-8 cycloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, Ci_-6 alkoxy, Ci_-6 aralkyl, C_2-6 aralkenyl, aryl or C_2-6 heterocyclic group; b) reducing in situ the compound of Formula XIV with a reducing agent in an alcoholic solvent to form a compound of Formula VIII:

Formula VIII

wherein:

Ri, R₂ and R₃ are as defined above; c) reacting the compound of Formula VIII in situ with a third N-acylating agent to form an oxazolidine protected aminodiol compound of Formula XII:

^{Formula XI1}

wherein:

Ri, R2, R3 and R₇ are as defined above; d) fluorinating the compound of Formula V with a fluorinating agent in the presence of an organic solvent to obtain a compound of Formula XIII:

Formula XIII

wherein: Ri, R2, R3 and R₇ are as defined above; and e) selectively hydrolyzing the compound of Formula XIII with an acid or base catalyst to form a compound of Formula Xl.

2. The process of claim 1 , wherein Ri is methylthio, methylsulfoxy, or methylsulfonyl.

3. The process of claim 2, wherein Ri is methylsulfonyl.

4. The process of claim 1 , wherein R₂ and R₃ are H, methyl, ethyl or propyl.

5. The process of claim 4, wherein R₂ and R₃ are methyl.

6. The process of claim 1 , wherein R5 is methyl, ethyl, n-propyl, isopropyl, butyl, t-butyl, or pentyl.

7. The process of claim 1, wherein R₇ is CH₂CI, CHCI₂, CCI₃, CH₂Br, CHBr₂, CBr₃, CH₂F, CHF₂, or CF₃.

8. The process of claim 1 , wherein the compound of Formula Vl is

9. The process of claim 8, wherein the compound of Formula Vl is

10. The process of claim 8, wherein the compound of Formula Vl is

11. The process of claim 1 , wherein the oxazolidine forming reagent is selected from the group consisting of formaldehyde, acetone, 2-methoxypropene, 2,2- dimethoxypropane, 2,2-diethoxypropane and mixtures thereof.

12. The process of claim 11 , wherein the oxazolidine forming reagent is 2,2- dimethoxypropane.

13. The process of claim 12, wherein the ratio of 2,2-dimethoxypropane to the compound of Formula Vl is between about 1 :1 and 5:1.

14. The process of claim 13, wherein the ratio of 2,2-dimethoxypropane to the compound of Formula Vl is about 1 :1.

15. The process of claim 1 , wherein the ester oxazolidine forming solvent is the oxazolidine forming reagent itself or an alcoholic solvent.

16. The process of claim 15, wherein the ester oxazolidine forming solvent is methanol, ethanol, propanol, isopropanol, butanol, pentanol and mixtures thereof.

17. The process of claim 16, wherein the ester oxazolidine forming solvent is methanol.

18. The process of claim 1 , wherein the ester oxazolidine promoting base is lithium carbonate, lithium carbonate, triethylamine or trimethylamine.

19. The process of claim 18, wherein the ester oxazolidine promoting base is lithium carbonate.

20. The process of claim 1 , wherein the ester oxazolidine promoting temperature is less than 80⁰C.

21. The process of claim 1 , wherein the compound of Formula XIV is:

22. The process of claim 1 , wherein the compound of Formula XIV is:

23. The process of claim 21 , wherein the compound of Formula XIV is:

24. The process of claim 22, wherein the compound of Formula XIV is:

25. The process of claim 23, wherein the compound of Formula XIV is:

26. The process of claim 24, wherein the compound of Formula XIV is:

27. The process of claim 1 , wherein the reducing agent is selected from the group consisting of NaBH₄, KBH₄, Ca(BH₄)2, and LiBH₄ and mixtures thereof.

28. The process of claim 27, wherein the reducing agent is KBH₄.

29. The process of claim 28, wherein the molar ratio of KBH₄ to the compound of Formula Vl is between about 1 :1 and 2:1.

30. The process of claim 29, wherein the molar ratio of KBH₄ to the compound of Formula Vl is about 1.5:1.

31. The process of claim 27, wherein the reduction is carried out at a temperature below 60⁰C.

32. The process of claim 31 , wherein the reduction is complete within 6 hours.

33. The process of claim 1 , wherein the alcoholic solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, pentanol, ethylene glycol, glycerin and mixtures thereof.

34. The process of claim 33, wherein the solvent is methanol or ethanol.

35. The process of claim 34, wherein the solvent is methanol.

36. The process of claim 1 , wherein the compound of Formula VIII is

37. The process of claim 36, wherein the compound of Formula VIII is

38. The process of claim 1 , wherein the third N-acylating agent is of the formula: formula R₆COR₇ wherein:

R₆ is halo or Ci_-6 alkoxy; and

R₇ is hydrogen, Ci_-6 alkyl, Ci_-6 haloalkyl, C_1-6 dihaloalkyl, Ci_-6 trihaloalkyl, C_3-8 cycloalkyl, C_3-8 cyclohaloalkyl, C_3-8 cyclodihaloalkyl, C_3-8 cyclotrihaloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, Ci_-6 alkoxy, Ci_-6 aralkyl, C_2-6 aralkenyl, C_2-6 heterocyclic, benzyl, phenyl or phenyl alkyl where the phenyl ring may be substituted by one or two halogens, Ci_-6 alkyl or Ci_-6 alkoxy.

39. The process of claim 38, wherein R₆ is Cl, Br, methoxy or ethoxy.

40. The process of claim 39, wherein R₆ is Cl.

41. The process of claim 38, wherein R₇ is CH₂CI, CHCI₂, CCI₃, CH₂Br, CHBr₂, CBr₃, CH₂F, CHF₂, or CF₃.

42. The process of claim 41 , wherein R₇ is CHCI₂.

43. The process of claim 38, wherein the third N-acylating agent is selected from the group consisting of methyldichloroacetate, ethyldichloroacetate, dichloroacetylchloride, methylchloroacetate, ethylchloroacetate, chloroacetylchloride, methyltrichloroacetate, ethyltrichloroacetate, trichloroacetylchloride, methyldifluoroacetate, ethyldifluoroacetate, difluoroacetylchloride, methylfluoroacetate, ethylfluoroacetate, fluoroacetylchloride, methyltrifluoroacetate, ethyltrifluoroacetate, trifluoroacetylchloride, dichloroacetylbromide, difluoroacetylbromide, acetylchloride, acetylbromide and mixtures thereof.

44. The process of claim 43, wherein the third N-acylating agent is methyidichloroacetate or dichloroacetylchloride.

45. The process of claim 44, wherein the third N-acylating agent is dichloroacetylchloride.

46. The process of claim 1 , wherein the third N-acylating base is selected from the group consisting of potassium carbonate, sodium carbonate, trimethylamine and triethylamine.

47. The process of claim 46, wherein the third N-acylating base is potassium carbonate or triethylamine.

48. The process of claim 47, wherein the molar equivalent ratio of the third N- acylating base to. the compound of Formula VIII is between 1 :1 and 3:1.

49. The process of claim 48, wherein the molar equivalent ratio of the third N- acylating base to the compound of Formula VIII is about 1.1 :1.

50. The process of claim 49, wherein the molar ratio of dichloroacetyl chloride to the compound of Formula VIII is between about 1 :1 and 3:1.

51. The process of claim 50, wherein the molar ratio of dichloroacetyl chloride to the compound of Formula VIII is about 1.1 to 1.

52. The process of claim 43, wherein the third N-acylation step is carried out at a temperature between 20 - 30⁰C.

53. The process of claim 52, wherein the third N-acylation reaction is complete within 2- 4 hours.

54. The process of claim 1 , wherein the compound of Formula XII is:

55. The process of claim 54, wherein the compound of Formula XII is:

56. The process of claim 54, wherein the compound of Formula XII is:

57. The process of claim 56, wherein the compound of Formula XII is:

58. The process of claim 1 , wherein the fluorinating agent is selected from the group consisting of N-(2-chloro-1 ,1 ,2-trifluoroethyl)diethylamine, N-(2-chloro-1 ,1 ,2- trifluor- oethyl)dimethylamine, N-(2-chloro-1 ,1 ,2-trifluoroethyl)dipropylamine, N-(2- chloro-1 ,1 ,2-trifluoroethyl)pyrrolidine, N-(2-chloro-1 ,1 ,2-trifluoroethyl)-2- methylpyrrolidine, N-(2-chloro-1 , 1 ,2-trifluoroethyl)-4-methylpiperazine, N-(2-chloro- 1 ,1 ,2-trifluoroethyl)- morpholine, N-(2-chloro-1 ,1 ,2-trifluoroethyl)piperidine, 1 ,1 ,2,2- tetrafluoroethyl-N,N-dimethylamine, (Diethylamino) sulfur trifluoride, Bis-(2- methoxyethyl)aminosulfur trifluoride, N,N-diethyl-1 ,1 ,2,3,3,3-hexafluoro-1- propanamine (Ishikawa Reagent) and mixtures thereof.

59. The process of claim 58, wherein the fluorinating agent is N,N-diethyl- 1 ,1 ,2,3,3,3-hexafluoro-i-propanamine.

60. The process of claim 59, wherein the molar ratio of N,N-diethyl-1 ,1 ,2,3,3,3- hexafluoro-1-propanamine to the compound of Formula XII is between about 1 :1 and 2:1.

61. The process of claim 60, wherein the molar ratio of N,N-diethyl-1 ,1 ,2,3,3,3- hexafluoro-1 -propanamine to the compound of Formula XlI is about 1.5:1.

62. The process of claim 61 , wherein the fluorinating step is carried out at a temperature of from about 80⁰C to about 110⁰C and at a pressure of about 60 psi.

63. The process of claim 1 , wherein the organic solvent is selected from the group consisting of 1 ,2-dichloroethane, methylene chloride, chloroform, chlorobenzene, chlorinated hydrocarbons and mixtures thereof.

64. The process of claim 63, wherein the organic solvent is methylene chloride.

65. The process of claim 1 , wherein the compound of Formula XIII is

66. The process of claim 65, wherein the compound of Formula XIII is

67. The process of claim 65, wherein the compound of Formula XIII is

68. The process of claim 67, wherein the compound of Formula XIII is

"-~- COCHCl₂

69. The process of claim 1 , wherein the compound of Formula Xl is

70. The process of claim 69, wherein the compound of Formula Xl is Florfenicol

71. The process of claim 1 , wherein the acid catalyst is, dilute aqueous hydrochloric acid, sulfuric acid, or phosphoric acid, methanesulfonic acid or p- toluene sulfonic acid.

72. The process of claim 71 , wherein the acid catalyst is p-toluene sulfonic acid.

73. The process of claim 1 , wherein the base catalyst is LiOH, NaOH, KOH,

Li₂CO₃, Na₂CO₃, K₂CO₃, sodium methoxide, sodium ethoxide, potassium methoxide and potassium ethoxide.

74. The process of claim 73, wherein the base catalyst is K₂CO₃.

75. The process of claim 74, wherein the temperature of the selective hydrolysis is below 8O⁰C.

76. The process of claim 1 , wherein methylene chloride is the organic solvent for the selective hydrolysis.

77. The process of claim 1 , wherein the compound of Formula Xl is purified with a mixture of a Ci-I₀ alkyl mono, di or tri alcohol and water to form the pure form of a compound of Formula Xl.

78. The process of claim 77, wherein the purification is carried out in a mixture of methanol, ethanol, propanol, iso-propanol, butanol, sec-butanol, t-butanol, pentanol, ethylene glycol, propylene glycol, butylene glycol or glycerin and water.

79. The process of claim 78, wherein the purification is carried out in a mixture of methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, t-butanol, or pentanol and water.

80. The process of claim 79, wherein the purification is carried out in a mixture of isopropanol and water.

81. The process of claim 80, wherein the ratio of isopropanol to water is between 1 :5 and 5:1.

82. The process of claim 81 , wherein the ratio of isopropanol to water is 1 :1.

83. The process of claim 82, wherein the dissolution temperature for purification is the reflux point of 1 :1 isopropanol and water.

84. The process of claim 77, wherein the purification reaction is cooled to 10 - 30⁰C to crystallize the desired compound.

85. The process of claim 84, wherein the purification reaction is cooled to about 20 - 25°C to crystallize the desired compound.